PROJECT SUMMARY/ABSTRACT - PROJECT 2 Reported prevalence of cognitive impairment in SLE ranges from 30-80% and behavioral alterations range from 17-75% with significant effects on quality of life and individual productivity. A hypothesis of this Program Grant is that autoantibodies cross-reactive with dsDNA and NMDA receptors, DNRAbs, contribute to cognitive and behavioral impairment in SLE patients. The goals of Project 2 are to continue development of FDG-PET as a biomarker for cognitive and behavioral impairment in NPSLE and to utilize other novel imaging techniques to enhance our understanding of pathologic mechanisms related to DNRAb effects on the brain. Cross-sectional FDG-PET studies of resting brain glucose metabolism demonstrate abnormal hypermetabolism in the hippocampus of SLE subjects. Hippocampus hypermetabolism and elevated serum titers of DNRAb combined have a higher predictive value for memory impairment than either variable alone. This is the first example of a consistent and robust imaging finding that reflects both impaired functional status and a proposed pathogenic mechanism in NPSLE. The longitudinal study proposed in Project 2 will validate and extend these associations. Subjects in the SLE cohort will be selected to have a range of serum DNRAb titers that is equally distributed across a spectrum of normal to high titers. The proposed longitudinal study will inform us about correlates of cognitive and behavioral change over time using FDG-PET imaging (Aim 1). Additionally, we will explore NMDAR biology in human subjects with a novel PET ligand, [11C]-CNS5161, used to localize and quantify NMDAR activation (Aim 2) and explore the role of blood brain barrier (BBB) integrity in cognitive and behavioral impairment (Aim 3). These studies complement the studies proposed in Project 1 that will explore the molecular and cellular basis for the hippocampal hypermetabolism in mouse models where tissue is readily available. In conducting these longitudinal studies, we will also determine the best biomarker with sensitivity for disease progression that can be used as a metric for a clinical trial.